Efficient Large-Scale Synthesis of a 2,4,5-Triarylimidazoline MDM2 Antagonist

An improved, kilogram-scale synthesis of a triarylimidazoline MDM2 antagonist is reported. The nicotinic acid component was prepared in three steps from ethyl 2-dimethylaminomethylene-3-oxo-butyrate. The coupling of the nicotinic acid with the meso-diamine selectively produced the monoamide which was cyclized in the presence of p-TSA/pyridine to give the imidazoline core. Phosgenation using bis(trichloromethyl) carbonate provided the key carbamoyl chloride intermediate, which was coupled with the side-chain amine, followed by chiral resolution with (R)-camphorsulfonic acid to give the final API.